Stephen Cullen

Mentor: Gregory K. Friestad, PhD

Year Entered Into Program: 2015

Terminal Degree(s) Received and Year: PhD 2020

Affiliations

Chemistry

Research Description

Applications of the Radical-Polar Crossover Reaction to Medicinal Chemistry

Previous work done in the Friestad Research Group has yielded an effective methodology for radical additions to imines with the use of a manganese (Mn) complex to generate an alkyl radical.1 This Mn-mediated radical addition is an effective way to generate carbon-carbon bonds. In the presence of UV light, Mn2(CO)10 cleaves to form two Mn(CO)5 radicals (Scheme 1). The cleavage of a carbon-iodine bond results in the formation of MnI(CO)5 and an alkyl radical. The imine carbon acts a radical acceptor, resulting in the formation of a new carbon-carbon bond and a nitrogen radical. The nitrogen radical abstracts a hydrogen from the H-donor to generate the new hydrazide. Recently, work has been done to use a radical addition in tandem with a nucleophilic attack by the lone pair on the nitrogen to form heterocyclic structure.2 This reaction is called the radical-polar crossover (RPC) reaction. The RPC reaction has already been used to synthesize various piperidine and pyrrolidine structures with high yields and good stereoselectivity (Scheme 2). An alkyl chain containing an iodine and a chlorine is a desirable substrate for the RPC reaction because of the ability to generate a radical from the iodine and he ability of chlorine to function as a leaving group. The alkyl radical is generated at the carbon bearing the iodine and adds to the imine carbon to form a hydrazide. The lone pair of  electrons from the nitrogen then attacks in an SN2 fashion at the carbon bearing the chlorine leaving group, forming the heterocycle. The chiral auxiliary directs the radical addition, allowing for a highly stereoselective reaction. Piperidines and pyrrolidines are frequently recurring motifs in natural products, so simple and reliable syntheses of these structures could be beneficial to the realm of medicinal chemistry. One of several future directions of the project is to examine what variety of substitution patterns can be observed on the product heterocycles using the RPC reaction with substituted chains on the dihalide.

Working in conjunction with the Pieper Research Group, another future direction of the RPC reaction has been targeted. The Pieper group has discovered a molecule, referred to as P5C6, which is being studied as a potential treatment for obsessive-compulsive disorder (Scheme 3).3 Analogs of P5C6 could show more potency and stability, while also allowing for more effective transfer across the blood-brain barrier. Other analogs could also be used to better understand  the mechanism of action of P5C6 to determine how it suppresses compulsive behaviors. A new synthetic route featuring the RPC reaction to the core of P5C6 analogs has been envisioned (Scheme 4). By replacing some of the nitrogen atoms with saturated hydrocarbons, the compound would be more lipophilic, enhancing transfer across the blood-brain barrier. The core structure could also be useful in natural product synthesis. The RPC step highlighted in Scheme 4 is different than previous examples shown since there is no nucleophilic attack by the nitrogen. Instead, nucleophilic attack occurs via a Friedel-Crafts alkylation to form the heterocycle. This type of RPC reaction has already been applied successfully to enamides (Scheme 5) and is a very promising alternative for this type of transformation.4 The RPC reaction could effectively yield a plethora of different P5C6 analogs to be studied.  Having access to a wide spectrum of analogs would be beneficial to study, and the RPC is the means by which this is possible. It is the hope that the results of this study will bring us closer to more effective and safer treatment not only for obsessive-compulsive disorder, but other neurological ailments as well.

The early stages of the RPC project are presently in motion. The first step is to synthesize considerable amounts of an Evans oxazolidinone auxiliary (Scheme 6). The auxiliary directs the stereochemistry of the radical additions shown above.2 The purity of the oxazolidinone is essential as well. Any remaining diethyl carbonate in the oxazolidinone crystals could potentially interfere with later steps. Once enough pure auxiliary is synthesized, it can be used to synthesize structures such as an Nacylhydrazone to be used in the study of piperidines and pyrrolidines (Scheme 6).

 

References

  1. Friestad, G. K.; Draghici, C.; Sourki, M.; Qin, J. J Org Chem 2005, 70, 6330-6338.
  2. (a) Slater, K.; Friestad, G. K. J Org Chem 2015, 80 (12), 6432-40. (b)Friestad, G. K.; Ji, A.; Korapala, C. S.; Qin, J. Org Biomol Chem 2011, 9 (11), 4039-43.
  3. Pieper, A. A.; Xie, S.; Capota, E.; Estill, S. J.; Zhong, J.; Long, J. M.; Becker, G. L.; Huntington, P.; Goldman, S. E.; Shen, C. H.; Capota, M.; Britt, J. K.; Kotti, T.; Ure, K.; Brat, D. J.; Williams, N. S.; MacMillan, K. S.; Naidoo,
  4. Melito, L.; Hsieh, J.; De Brabander, J.; Ready, J. M.; McKnight, S. L. Cell 2010, 142 (1), 39-51.
  5. Friestad, G. K.; Wu, Y. Org Lett 2009, 11 (4), 819-822.

Awards

  • Institutional support on the Pharmacological Sciences Training Program (NIH T32 GM067795), University of Iowa, 2017-present
  • Fellowship appointment on the Pharmacological Sciences Training Program (NIH T32 GM067795), University of Iowa, 2016-2017

Publications

  1. Cullen S.T.J., and Friestad, G.K.: Alkyl Radical Addition to Aliphatic and Aromatic N-Acylhydrazones Using an Organic Photoredox Catalyst. Org Lett 21(20:8290-8294, 2019.  PMCID: PMC6900872

Research